The goal is to study the biochemical mechanisms of endotoxin-induced lung injury. Based on our previous work, we postulated a central role for platelet activating factor (PAF) in endotoxemia. PAF, which is produced early in endotoxemia, may stimulate neutrophils and other effector cells to release toxic substances such as oxygen radicals and lysosomal proteins and enzymes, thus injuring the pulmonary vasculature. In addition, PAF may act directly to caused increased vascular permeability and shock. The initial set of studies will characterize the interaction between oxidants and lung glutathiones, an important intracellular antioxidant system, in two separate ways. First, measurements of the oxidized glutathione in plasma and lung tissue will be used as an index of oxidant stress. Secondly, lung glutathione content will be modulated by disrupting specific steps in the glutathione redox cycle. The effect of these interventions on the severity of lung injury should clarify the role of oxidants in endotoxin lung injury. Subsequent studies will address the hypothesis that PAF is a crucial mediator using PAF depleted rats as well as synthesis inhibitors and receptor antagonists of PAF. Whether PAF acts by stimulating the release of oxidants from effector cells such as neutrophils will also be studied. Finally, we plan to assess the contribution of the non-oxidant neutrophil products to endotoxin lung injury. The work is based on a small animal model of endotoxemia in which systemic and pulmonary hemodynamic and lung vascular permeability changes can be conveniently measured. In addition, measurements of lung tissue glutathiones, arachidonate metabolites, and PAF will be performed in our laboratory. The result from these studies should better define the biochemical changes and mechanisms of endotoxemia and hopefully improve our understanding of the pathogenesis of human adult respiratory distress syndrome.